ALMS1-Deficient Fibroblasts Over-Express Extra-Cellular Matrix Components, Display Cell Cycle Delay and Are Resistant to Apoptosis

作者：Zulato Elisabetta^*; Favaretto Francesca; Veronese Caterina; Campanaro Stefano; Marshall Jan D; Romano Sara; Cabrelle Anna; Collin Gayle B; Zavan Barbara; Belloni Anna S; Rampazzo Enrica; Naggert Juergen K; Abatangelo Giovanni; Sicolo Nicola; Maffei Pietro; Milan Gabriella; Vettor Roberto

来源：PLos One, 2011, 6(4): e19081.

DOI：10.1371/journal.pone.0019081

Alstrom Syndrome (ALMS) is a rare genetic disorder (483 living cases), characterized by many clinical manifestations, including blindness, obesity, type 2 diabetes and cardiomyopathy. ALMS is caused by mutations in the ALMS1 gene, encoding for a large protein with implicated roles in ciliary function, cellular quiescence and intracellular transport. Patients with ALMS have extensive fibrosis in nearly all tissues resulting in a progressive organ failure which is often the ultimate cause of death. To focus on the role of ALMS1 mutations in the generation and maintenance of this pathological fibrosis, we performed gene expression analysis, ultrastructural characterization and functional assays in 4 dermal fibroblast cultures from ALMS patients. Using a genome-wide gene expression analysis we found alterations in genes belonging to specific categories (cell cycle, extracellular matrix (ECM) and fibrosis, cellular architecture/motility and apoptosis). ALMS fibroblasts display cytoskeleton abnormalities and migration impairment, up-regulate the expression and production of collagens and despite the increase in the cell cycle length are more resistant to apoptosis. Therefore ALMS1-deficient fibroblasts showed a constitutively activated myofibroblast phenotype even if they do not derive from a fibrotic lesion. Our results support a genetic basis for the fibrosis observed in ALMS and show that both an excessive ECM production and a failure to eliminate myofibroblasts are key mechanisms. Furthermore, our findings suggest new roles for ALMS1 in both intra-and extra-cellular events which are essential not only for the normal cellular function but also for cell-cell and ECM-cell interactions.

• 出版日期2011-4-26